I. Field of the Invention
The invention generally relates to the fields of molecular biology and oncology.
II. Related Art
Cancer is the result in the occurrence of multiple factors. Mutations may occur in proto-oncogenes that cause cellular proliferation to increase. Mutations also may occur in tumor suppressors whose normal function is to regulate cellular proliferation. Mutations in DNA repair enzymes impair the ability of the cell to repair damage before proliferating. Tumor suppressor genes are normal genes whose absence (loss or inactivation) can lead to cancer. Tumor suppressor genes encode proteins that slow cell growth and division. Cancer arises when there is a mutation in both alleles.
Tumor suppressor genes (TSGs) play a major role in the pathogenesis of human lung cancer and other cancers. Lung cancer cells harbor mutations and deletions in multiple known dominant and recessive oncogenes6,7. Known TSGs such as Rb, p53, and putative TSGs have been found at chromosome regions 3p, 5q, 6p, 8p, 9p, and 11p as well as other sites6,8,9. Cytogenetic and allelotyping studies of fresh lung tumors and tumor cells showed tumor-cell allele loss at multiple sites, suggesting the existence of one or more such TSGs6-8,10. However, cytogenetic changes and allele loss on the short arm of chromosome 3 (3p) have been shown to be most frequently involved in about 90% of small cell lung cancers (SCLCs) and >50% of non-small cell lung cancers (NSCLCs)6,8,10,11. SCLC and NSCLC are the two treatment groups of lung tumors and are made up of four histological types. Squamous cell-, adeno-, and large cell carcinomas are in the NSCLC group. Small cell lung cancer is in the SCLC group. Approximately 75% of lung tumors are NSCLCs. Metastases occur later with NSCLC than with SCLC. SCLC is one of the most metastatic of solid tumors52. In addition, similar 3p changes have been seen in several other cancers in addition to lung, such as renal12,13, breast14,15, head and neck16, pancreatic17, kidney18, oral19, and uterine cervical cancers20,21. Furthermore, a group of TSGs, as defined by homozygous deletions in lung cancers, have been located and isolated at 3p21.3 in a 450-kb region6,10,22-24. Studies of lung cancer preneoplasia indicate that 3p21 allele loss is the earliest genetic abnormality in lung cancer detected so far, occurring in hyperplastic lesions; this shows that one or more 3p-recessive oncogenes function as “gatekeepers” in the molecular pathogenesis of many human cancers, including lung cancer, where it is likely to be involved in >50% of all cases6,10,22-26.
Recently, human chromosome band 3p21.3 has been shown to undergo overlapping homozygous deletions in several SCLC and NSCLC lines; candidates of TSGs have been located in this critical region in several human cancers, further defining a TSG region6,10,24,27. The evidence shows that genes in this 3p21 critical region are involved in regulation of the telomerase-mediated cellular immortality pathway in lung, renal, and breast cancer cells28,29. It has also been shown that 3p deletion occurs more frequently in the lung tumor tissues of patients who smoke. In addition, elevated sensitivity to the carcinogen benzo[a]pyrene diol epoxide at 3p21.3 has been associated with an increased risk of lung cancer, suggesting that 3p21.3 is a molecular target of carcinogens in lung cancer31. Despite those studies, there remains a need to further identify the functions of these genes and demonstrate their involvement with cancer.